Project summary Lung cancer is the leading cause of cancer death worldwide, largely due to its highly metastatic nature. Hence, elucidating the molecular mechanisms for tumor metastasis remains one of the most pressing challenges in lung cancer research. To date, most studies on cancer metastasis have focused on protein-coding genes, yet it has become increasingly clear that non-coding RNAs, particularly, microRNAs (miRNAs), are integral components of the molecular network for cancer metastasis, Using a Kras-driven, p53 deficient lung adenocarcinoma mouse model, we compared the miRNA expression profiles between primary and metastatic lung tumors, and identified miR-200 miRNAs as the most downregulated miRNAs in lung cancer metastases. The miR-200 family consists of five homologous miRNAs located at two genomic loci: mir- 200b/200a/429 and mir-200c/141. To characterize miR-200 functions in lung cancer metastasis, we generated KrasLSL-G12D/+;p53fl/fl; mir-200c/141-/- (KP200cKO) mice, which exhibited a significant increase of tumor metastases within a short latency. Interestingly, all metastatic KP200cKO tumors examined exhibited a complete silencing of all miR-200 miRNAs, suggesting that a complete loss of miR-200 redundancy was essential for developing cancer metastasis in this model. Based on these preliminary findings, we hypothesize that miR-200 miRNAs are key repressors of cancer metastasis in Kras-driven, p53 deficient lung adenocarcinomas. Using mouse genetics, CRISPR genome editing, cell and molecular approaches, we propose to comprehensively characterize the importance of miR-200 miRNAs during lung cancer metastasis, and will elucidate the underlying molecular and cellular mechanisms that govern the biological functions and transcriptional regulation of miR-200 miRNAs. Our proposed studies will provide important insights into a highly robust mechanism to repress lung cancer metastasis.